Dienophiles imino

Acylation of 3-arylamino-4-arylimino-4//-pyrido[l,2-u]pyrazines (373) with acyl chlorides afforded mixtures of mono- and bisacylated derivatives 374 and 375 (99JPR332). Acetyl chloride gave only monoacylated product 374 (R = 4-MePh, R =Me). Bis-acylated derivative 375 (R = 4-MePh, r = Me) was obtained in 68% yield in boiling toluene. Reaction of 373 with dienophiles 376 and 377 gave 4-thiono and 4-seleno derivatives of 4//-pyrido[l,2-u]pyrazines 378 (Y==S, Se) and 4-imino-4//-pyrido[l,2-u]pyrazines 379, respectively (99JPR332). 

Aza Diels-Alder Reactions of Azadienophiies 193 Tab, 5,3 Catalytic enantioselective aza Diels-Alder reactions using imino dienophiles (1)... 

The first enantioselective aza-Diels-Alder reactions of imino dienophiles on use of a chiral zirconium catalyst [116]... 

Diels-Alder, imino dienophiles, 65, 2 Diels-Alder, intramolecular, 32, 1 Diels-Alder, maleic anhydride, 4, 1 [4 -h 3], 51, 3 of enones, 44, 2 of ketenes, 45, 2 of nitrones and alkenes, 36, 1 Pauson-Khand, 40, 1 photochemical, 44, 2 retro-Diels-Alder reaction, 52, 1 53, 2 [6-h4], 49, 2 [3-h2], 61, 1 Cyclobutanes, synthesis ... 

Imidates, rearrangement of, 14, 1 Imines, additions of allyl, allenyl, propargyl stannanes, 64, 1 additions of cyanide, 70, 1 as dienophiles, 65, 2 synthesis, 70, 1 Iminium ions, 39, 2 65, 2 Imino Diels-Alder reactions, 65, 2 Indoles, by Nenitzescu reaction, 20, 3 by reaction with TosMIC, 57, 3 Ionic hydrogenation, 71, 1 Isocyanides, in the Passerini reaction, 65, 1... 

Although several Lewis acids are known to catalyze the hetero-Diels-Alder reaction involving imino-dienes or imino-dienophiles (aza-Diels-Alder reaction), a large amount of the catalyst is often necessary. Bi(0Tf)3-xH20 showed higher activity than lanthanide triflates in catalyzing the reactions of imines with Danishefsky s diene (Scheme 15) [72]. 

The precursor to (5) was made diastereoselectively by Fessner and coworkers [44]. When the intermediate ketose 1-phosphate was immediately submitted to hydrogenation conditions, l,5,6-trideoxy-l,5-imino-D-galactitol (1,6-dideoxygalactonojirimycin, 10) was obtained in fair yield [42]. The latter derivative was also obtained by a hetero Diels-Alder cycloaddition of a benzyloxycarbonyl nitroso dienophile to ( , )-sorbaldehyde dimethylacetal [45]. 

A synthesis of ( )-tylophorine (213) has been based on the discovery that vanadyl trifluoride (VOF3) can be used to convert 1,2-diarylethylene into phenanthrenes in high yield. In the top sequence shown in Scheme 34, ring closure is accompanied by dehydrogenation (77CC826). In a second synthesis, ( )-tylophorine (213) is the result of an intramolecular version of a Diels-Alder cycloaddition of a conjugated diene with an imino dienophile (Scheme 34, lower sequence) (79JA5073). 

The benzyne route to 1-cyanobenzocyclobutenes has been employed for the synthesis of a myriad of complex natural products. The cyano group in (74) was used to attach the dienophile as well as for building die imino bridge of (75), an important precursor for some diterpene alkaloids (Scheme 15).110... 

The formation of tetrahydropyridines by reaction of a suitable diene with an imino dienophile is a reaction known since more than half a century [177] and has been intensively studied. In general, the imines react as the electron-deficient component and their reactivity strongly depends on the electron density which may be tuned by activating or deactivating moieties. However, exceptions from this rule are possible as found by Padwa et al. [178]. They described cycloadditions of imines to bis(phenylsulfonyl)-1,3-butadienes. 

Hetero Diels-Alder reactions with imino dienophiles have been employed as key step in several syntheses of naturally occuring alkaloids. With regard to stereoselective transformations, the approach to (S)-anabasin worked out by Kunz et al. impressively illustrates the high utility of natural carbohydrates as source of chirality in asymmetric synthesis [505]. The N-galactosyl imine 7-28 underwent a Lewis acid catalysed aza Diels-Alder reaction with Danishefsky s diene which proceeded with excellent induced diastereoselectivity to yield the adduct 7-29. A short sequence then afforded the desired alkaloid 7-30. This work also deals with the suitability of several other dienes and imino dienophiles for such transformations (Fig. 7-7). 

Two very elegant alkaloid syntheses basing on intramolecular cycloadditions of imino dienophiles have been published by Grieco and his coworkers. The preparation of ( )-eburnamonine 7-32 is very efficient since imine 7-31, available from (5-valerolactam in a straightforward sequence, is directly converted into the desired alkaloid 7-32 by aza Diels-Alder reaction and subsequent isomerisation of the newly formed double bond. (Fig. 7-8) [506],... 

Further applications of imino dienophiles to the synthesis of natural or biologically active compounds have been directed to (-)-cannabisativine [508] and HIV-1 protease inhibitors [509] Bailey s investigations of the enantioselective synthesis of pipecolic acid derivatives have already been discussed in Sect. 3.1. 

A subset of imino-Diels-Alder cycloadditions involving reactions between N-aryl imines and electron-rich dienophiles is the Povarov reaction [75]. 

Nitrosoimines 6, prepared by oxidation of the corresponding imino oximes, are also effective as dienophiles in the hetero-Diels-Alder cycloaddition2. 

As a rule, cycloadditions with acyclic -acyl imino dienophiles are useful synthetic reactions which demonstrate excellent regio- and stereo-selectivity. A commonly used source of IV-acyl immonium dienophiles are bis-urethanes such as (13) (equation S), which upon treatment with a Lewis acid and a diene afford Diels-Alder adducts. In this case, (13) reacts with boron trifluoride etherate to afford immonium ion (14) which adds to diene (15), yielding tetrahydfopyridine (16). ... 

A few instances of neutral acyclic A(-acyl imino dienophiles have been reported. Some of these imines can be prepared and isolated, but often they are generated in situ. For example, Wittig chemistry... 

A number of diverse stmctural types of cyclic imino dienophiles have been used in cycloadditions. For instance, dehydrohydantoins are useful partners in hetero Diels-Alder reactions. Two methods have been developed for in situ generation of these species. In one tqjproach, methoxyhydantoins such as (24) (equation S) are heated or are treated with acid to promote elimination of methanol, affording dienophile (25).22- This intermediate can be trapped regio- and stereo-selectively with 1,3-dienes. For example, with 1,3-cyclohexadiene only endo adduct (26) is formed. There is no ambiguity in this case concerning the dienophile configuration, and thus product (26) clearly derives from an endo transition state. 

Recently, a few examples of imino Diels-Alder reactions using azetinones as dienophiles have been described in work aimed at synthesis of carbapenems. In one sequence of reactions, acetate (34) was treated with a Lewis acid in the presence of a siloxy diene to afford adduct (36) (equation ll). This transformation presumably involves imine (35) which reacts both regio- and stereo-selectively with the diene. Adduct (36) was converted in a few steps to carbapenem (37). 

Bis-imines (117) have been used far less than the monoimines as dienophiles. However, there are enough examples of these cycloadditions to indicate clearly that they are regioselective and, provided at least one electron-withdrawing group is present on nitrogen, that they proceed under mild reaction conditions. As with the monoimines, little is known with regard to the establishment of sulfur stereochemistry in the dihydrothiazine imines (118). Equations (55)," (56) and (57) demonstrate both the regio-selectivity of the process and some of the structural types of bis-imino compounds which have been... 

Imines are also potential dienophiles in hetero-Diels-Alder reactions. Jprgensen et al. have evaluated Cu(I) Lewis acids in enantioselective imino Diels-Alder reactions (Sch. 52) [98]. 

As for the oxo-Diels-Alder reaction, not much has been reported other Lewis acids are usually superior [26]. As for the aza-Diels-Alder reaction, enantioselective reactions between imino dienophiles 60 and diene 61, using a chiral binaphtholzirco-nium catalyst 23, are known (Eq. 26) [27]. 

Methylated and unmethylated methoxyazocine appear, on the basis of their chemistry and spectroscopy, to exist in the tub conformation (39), similar to cyclooctatetraene. These compounds react with dienophiles and potassium f-butoxide to give Diels-Alder adducts and benzonitriles, respectively, presumably via an azabicyclo[4.2.0]octane isomer (40). The properties of 39 indicate that the methoxy group is attached to the imino and not an olefinic carbon. This has been confirmed by recent ab initio calculations.69... 

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